Dithiocarbonylthioacetyl cephalosporins

ABSTRACT

Dithiocarbonylthioacetylcephalosporins of the general formula   WHEREIN R is hydrogen, lower alkyl, aralkyl, tri(lower alkyl)silyl, a salt forming ion, or the group   D R A W I N G

United States Patent [1 1 Treuner et al.

[ Nov. 5, 1974 l 54 DITHIOCARBONYLTHIOACETYL CEPHALOSPORINS [75] Inventors: gwe Treuner, Regensburg;

ermann Breuer, Burgweinting, both of Germany [73] Assignee: E. R. Squibb & Sons, Inc.,

Princeton, NJ.

[22] Filed: July 17, 1972 [21] Appl. No.: 272,228

Related U.S. Application Data [63] Continuation-impart of Ser. No. l80,523, Sept. 14,

i971, abandoned.

[52] U.S. Cl. 260/243 C, 424/246 [51] Int. Cl C07d 99/24 [58] vField of Search 260/243 C [56] References Cited UNITED STATES PATENTS 3,574,190- 4/1971 Honkanen et al. 260/239.]

Primary ExaminerNicholas S. Rizzo Attorney, Agent, or Firm-Lawrence S. Levinson; Merle J. Smith [571 ABSTRACT Dithiocarbonylthioacetylcephalosporins of the general formula lower alkenyl, cycle-lower alkadienyl, aralkyl, aryl or certain heterocyclic groups; R is a salt forming ion, lower alkyl, cyclo-lower alkyl, aryl or aralkyl; R is lower alkyl, aryl or aralkyl; and X is hydrogen, hydroxy, lower alkanoyloxy, aroyloxy, aralkanoyloxy, the radical of a nitrogen base, a quaternary ammonium radical, or together X and R represent a bond linking carbon and oxygen in a lactone ring; are useful as antibacterial agents. 7

8 Claims, N0 Drawings DITHIOCARBONYLTHIOACETYL CEPHALOSPORINS This application is a continuation-in-part of application Ser. No. 180,523, filed Sept. 14, 1971, now abandoned.

SUMMARY OF THE INVENTION This invention relates to new dithiocarbonylthioacetylcephalosporins of the formula I R represents hydrogen, lower alkyl, aralky, tri-(lower alkyl)silyl, a salt forming ion or the group H CH C R I R represents hydrogen, aryl, lower alkyl, cyclo-lower alkyl, cyclo-lower alkenyl, cyclo-lower alkadienyl, aralkyl or certain heterocyclic groups; R represents a salt forming ion, lower alkyl, cyclo-lower alkyl, aryl or aralkyl; R represents lower alkyl, aryl or aralkyl. X is hydrogen, hydroxy, lower alkanoyloxy, aroyloxy, aralkanoyloxy, the radical of a nitrogen base, a quaternary ammonium radical, or together X and R represent a bond linking carbon and oxygen in a lactone ring.

The preferred members within each group are as follows: R is hydrogen, lower alkyl, alkali metal, trimethylsilyl or p -crr -o-d-R especially hydrogen, methyl, pivaloyloxy, sodium or potassium; R is hydrogen, lower alkyl, phenyl, thienyl, furyl, oxazolyl, isoxazolyl or thiazolyl, especially phenyl; R is loweralkyl, especially methyl or ethyl; R is lower alkyl, preferably methyl or t-butyl and X is preferably hydrogen or acetoxy.

DETAILED DESCRIPTION OF THE INVENTION The various groups represented by the symbols have the meanings defined below and these definitions are retained throughout this specification.

and bromine being preferred), lower alkyl groups such I as those defined above, lower alkoxy groups, (i.e.,

lower alkyl groups of the type defined above attached to an oxygen), hydroxy, carboxy and the like. In the case of the last two named substituents there is prefera- 3,4,5-trimethoxyphenyl,

nyl,'lllustrative are phenyl, 0-, mand p-chlorophenyl, o-, mand p-bromophenyl, 3,4-dichlorophenyl, 3,5- dibromophenyl, o-, mand p-tolyl, p-methoxyphenyl,

p-hydroxyphenyl, pcarboxyphenyl and the like.

The aralkyl groups include a monocyclic carbocyclic aryl group attached to a lower alkyl group, both as defined above. Illustrative are benzyl, o-, mor pchlorobenzyl, o-, mor p-bromobenzyl, 0-, mor pmethylbenzyl, phenethyl, p-chlorophenethyl, 3,5- diethylbenzyl, 3,4,5-trichlorobenzyl and the like.

The lower alkanoyloxy, aroyloxy and aralkanoyloxy groups represented by X include the acyl group of acid esters. The lower alkanoyl radicals are the acyl radicals of lower fatty acids containing alkyl radicals of the type described above. The lower alkanoyloxy groups include, for example, acetoxy, propionyloxy, butyryloxy and the like. The aroyloxy groups are derived from monocyclic carbocyclic aryl groups monocyclic carbocyclic aryl and alkanoyloxy the kind described. Similarly the aralkanoyloxy groups consist of type radicals of the type described. X also represents the radical of an amine, e.g., an alkylamine like methylamine, ethylamine, dimethylamine, triethylamine, aralkylamine like dibenzylamine, N,N-dibenzyl-pyridinium, pyridinium, l-quinolinium, l-picolinium, etc. X and R may also join together, as indicated above, to form a bond linking carbon and oxygen in a lactone ring.

The heterocyclic groups represented by R, are 5- to 6-membered monocyclic heterocyclic radicals (exclusive of hydrogen), including thienyl, furyl, oxazolyl, isoxazolyl and thiazolyl, as well as these heterocyclics with the substituents halo, lower alkyl (particularly methyl and ethyl), lower alkoxy (particularly methoxy and ethoxy) or phenyl.

The salt forming ions represented by R and R may be metal ions, e.g., aluminum, alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium, or an amine salt ion, of which a number are known for this purpose, for example, dibenzylamine, N,N-dibenzylethylene-diamine, methylamine, triethylamine, procaine, N-ethylpiperidine, etc.

The new dithiocarbonylthiocetylcephalosporins of this invention are produced by reacting a 7-aminocephalosporanic acid compound of formula II [which includes 7-aminocephalosporanic acid (7-ACA), 7- amino-3-desacetoxycephalosporanic acid (7-ADCA) and other derivatives] of the formula H N-f TH CH with a dithiocarbonylthioacetic acid of the formula (III) a ea-coon or an activated derivative of the former (II). The symbols have the meanings already defined.

The activated derivatives refered to include, for example, the reaction product with an anhydride forming reagent such as ethylchloroformate, benzoyl chloride, pivaloyl chloride, etc., or with bis-imidazolecarbonyl, dicyclohexyl-carbodiimide, p-nitrophenol or the like.

The reaction between 7-aminocephalosporanic acid compound and the dithiocarbonylthioacetic acid may be effected, for example, by dissolving or suspending the latter in an inert organic solvent such as chloroform, methylene chloride, dioxane, benzene or the like, and adding, at about room temperature or below, about an equimolar amount of an anhydride forming reagent, e.g., ethyl chloroformate,'benzoylchloride or the like, or other activating compound such as dicyclohexylcarbodiimide, along with a salt forming organic base, such as triethylamine, pyridine or the like, followed, after an interval, by the addition of the 7-aminocephalosporanic acid compound. The product of the reaction is then isolated by conventional procedures, e.g.,

by concentration or evaporation of the solvent.

When R is the acyloxymethyl group ll --C-R wherein hal is halogen, preferably chlorine or bromine, in an inert organic solvent such as dimethylformamide, acetone, dioxane, benzene or the like, at about ambient temperature or below.

As an alternative, a product of formula I may be produced by reacting a salt, e. g., an alkali metal salt, of the formula with a compound of the formula or derivative thereof in a solvent such as dimethylformamide. Me represents a metal, hal is halogen, preferably chlorine or bromine and R and R are the same as above.

The dithiocarbonylthioacetic acid of formula Ill may a ea-coca,

I MeB-C -R u i/ s R -CH-COOH by a procedure analogous to that described by Bonner, Jour. Org. Chem. 33, 1831 (1968).

The symbols have the meanings already defined.

Further process details are also provided in the illustrative examples.

Certain of the compounds of this invention may exist in different optically active forms. The various stereoisomeric forms as well as the racemic mixtures are within the scope of the invention.

The compounds of this invention have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureus, Salmonella schottmuelleri, Pseudomonas aeruginosa, Proteus vulgaris, Escherichia coli and Streptococcus pyogenes. They may be used as antibacterial agents in a prophylactic manner, e.g., in cleaning or disinfecting compositions, or otherwise to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to cephalothin and other cephalosporins. For example, a compound of formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about 1 to 200 mg./kg., daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mg./kg. in mice.

Oral forms give prompt high blood levels which are maintained for relatively long periods.

Up to about 600 mg. of a compound of formula I or a physiologically acceptable salt thereof may be incorporated in an oral dosage form such as tablets, capsules or elixirs or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice.

They may also be used in cleaning or disinfecting compositions, e.g., for cleaning barns or dairy equipment, at a concentration of about 0.01 to 1% by weight of such compounds admixed with, suspended or dissolved in conventional inert dry or aqueous carriers for application by washing or spraying. They are also useful as nutritional supplements in animal feeds.

The following examples are illustrative of the invention. All temperatures are on the centigrade scale. Additional variations may be produced in the same manner by appropriate substitution in the starting material.

EXAMPLE 1 D,L-7-[2-[[(Ethylthio)thiocarbonyl]thio]-2- phenylacetamido]-cephalosporanic acid and potassium salt 3.6 g. (10 mmol.) of DL-7-a- (bromophenylacetamido)cephalosporanic acid are dissolved in 15 ml. of absolute dimethyl-formamide and then 1.8 g. (10 ml.) of potassium ethyltrithionate, dissolved in 15 ml. of dimethylformamide are added with stirring. The temperature is controlled by cooling so that the mixture does not go above 40. After minutes, the reaction solvent is poured into 350 ml. of cold water and extracted twice with 200 ml. of ethyl acetate each time. The ethyl acetate extract is dried with so- 5 dium sulfate and distilled off in vacuo. The oily residue is crystallized by treatment with ether and petroleum ether. The product, DL-7-[2- (ethylthio )thiocarbonyl]thio]-2-phenylacetamido]cephalosporanic acid, is obtained in 83 percent yield, m.p. 7780. Solution of the acid in a small amount of n-butanol, addition of an equivalent amount of potassium 2-ethylhexanoate and then adding ether gives the potassium salt as a pale yellow powder, m.p. 148 (dec.). The sodium salt is formed similarly.

The following additional products are similarly obtained (melting points are for salt): 7-[2-[[(methylthio)thiocarbonyl]thio]-2- phenylacetamido]-cephalosporanic acid and potassium salt, m.p. 153 (dec.).

7- 2-[[(cyclohexylthio)thiocarbonyl1thio1-2- phenylacetamido]-cephalosporanic acid and potassium salt (hydrate), m.p. 143 (dec.).

7-[2-[(ethylthio)thiocarbonyl]thioacetamido]cephionate, the starting material (b) with the substituents indicated in the table:

s R -CHCONH s l I K-S-C-S-R2 R -cu-co-ma ca ca Ta N H2X I I o i gas-R c N c-ca x N 2 W 5 0 c l (b) (c) fi- 2 ca 3 I ca a on 3 e 3 cs c 5 4 CH3 C357 C255 pyr; lnlum 5 9 c 11 ca c n ca ococa 2 3 2 e 5 2 e s 2 :a

it 5 a ococa CH2O C-C6B5 4 clc ia 7 2 M. ?"."s?2a..; 2 s 7 i v.

8 a s (c) 3C6H2 2*,5 ococu C Na 9 Na 4 CH 6H4 OCQCI-I h n: (+10 ,4-(Br) C I-1 CH a an, HR)

11 c 3 2,4-(C1) c H CZHS an:

12 C2115 C H -u/|[ C li s C. H 13 c 5 I I 2 5 OCH:

a on 14 I CSHSCHZ C 5 2 omzcexs II II a O 15 cn oc-c (CH 3 c rt c 11 5 Table Continued Example R R1 R2 X 16 Si (CH3) 3 n-butyl H 17 B G 3 l8 H (1 1-15 ococn 19 K CH3 H 20 K E C6H5 a 21 n c a H 22 H s s OCOCI-I3 23 H I CH3 ococn What is claimed is: 2. A compound as in claim 1 wherein R is hydrogen, 1. A compound of the formula I R is phenyl and R is phenyl-lower alkyl.

- i 3. A compound as in claim 1 wherein R is potassium,

S R is phenyl, R is ethyl and X is acetoxy. RFCH CH 4. A compound as in claim 1 wherein R is alkali l I I 2 25 metal, R is phenyl, R is ethyl and X is lower als-c-s-R kanoyloxy.

ll N 5. A compound as in claim 1 wherein R is hydrogen, S o lower alkyl, alkali metal, trimethylsilyl or C-OR H CH 0 g R wherein R is hydrogen, lower alkyl, alkali metal, tri- R is phenyl, R is lower alkyl and Xis hydrogen or acemethyl-silyl or toxy, i 6. A compound as in claim 1 wherein R is hydrogen,

R is phenyl, R is lower alkyl and X is lower alkanoyloxy. 2 3 I 40 7. A compound as in claim 6 wherein the lower alkyl group is ethyl and the lower alkanoyloxy group is ace- R is phenyl; R is aluminum, alkali metal, alkaline. .toxy.

earth metal, lower alkyl, C -C cyclo-lower alkyl, phe- 8. A compound as in claim 1 wherein R is hydrogen, nyl or phenyl-lower alkyl, R is lower alkyl, phenyl or R is phenyl, R is lower alkyl or cyclohexy] and X is acphenyl-lower alkyl and X is hydrogen, hydroxy or lower ,etoxy,

alkanoyloxy. t

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,846,418 DATED November 5, 1974 V I Uwe Treuner, Hermann Breuer It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 19 "aralky" should be aralkyl Column 2, line 22 after of should be inserted monocyclic carbocyclic aryl and alkanoyloxy Column 2, lin delete "typ Erigncd and Scaled this Thirtieth Day of November 1976 [SEAL] Attest:

RUTH c. MASON c. MARSHALL DANN Arresting Officer Commissioner of Parents and Trademarks 

1. A COMPOUND OF THE FORMULA
 2. A compound as in claim 1 wherein R is hydrogen, R1 is phenyl and R2 is phenyl-lower alkyl.
 3. A compound as in claim 1 wherein R is potassium, R1 is phenyl, R2 is ethyl and X is acetoxy.
 4. A compound as in claim 1 wherein R is alkali metal, R1 is phenyl, R2 is ethyl and X is lower alkanoyloxy.
 5. A compound as in claim 1 wherein R is hydrogen, lower alkyl, alkali metal, trimethylsilyl or
 6. A compound as in claim 1 wherein R is hydrogen, R1 is phenyl, R2 is lower alkyl and X is lower alkanoyloxy.
 7. A compound as in claim 6 wherein the lower alkyl group is ethyl and the lower alkanoyloxy group is acetoxy.
 8. A compound as in claim 1 wherein R is hydrogen, R1 is phenyl, R2 is lower alkyl or cyclohexyl and X is acetoxy. 